It‘s all about drug-protein binding: fake antigen in drug allergy
A comparison of covalently and non-covalently linked drug-protein complexes points out that the kind of drug-protein binding may determine whether “silent” immunity or symptomatic allergy evolves.
Hapten-protein adducts, based on covalent bonds, represent novel antigens, which can induce a complex immune response, including IgE. IgE reactions are not per se “harmful”, even if we associate them with the very common, annoying allergies. The first encounter with the antigen is often unspectacular and sensitization remains unnoticed since sensitization goes along with MC-unresponsiveness. In most IgE-reactions, this tight control may persist and no symptoms appear.
Not only the induction of immune response but also the reaction at re-exposure may be mitigated by the type of antigen. The formation of covalent bonds is a comparatively slow process, and for some drugs, even a metabolic step is intermingled, before complex-formation can start. Moreover, the number of antigenic epitopes are limited to those protein sites able to accommodate covalent binding. Thus, if the IgE reactivity is directed to haptens exclusively, the formation of antigen-complexes is slow (hours) and the amount of antigen is limited. Both conditions would favor the induction of MC-unresponsiveness at re-exposure again and no symptoms would occur.
The situation is different if the non-covalent drug-protein complexes are
  1. relatively stable,
  2. can interact with preformed IgE, and
  3. even cross-link the FcεR-bound IgE:
Such complexes pretend to be relevant antigens but are in reality “fake antigens” . They are formed very rapidly and in high concentrations (see table 3) and thus overrule MC-unresponsiveness: an uncontrolled MC-degranulation/“fake-antigen reaction” (FAR)with urticaria, angioedema and anaphylaxis may occur (figure 3).